Pharmacokinetics of new calcium channel antagonist clevidipine in the rat,rabbit, and dog and pharmacokinetic/pharmacodynamic relationship in anesthetized dogs

Clevidipine is a new vascular selective calcium channel antagonist of the d ihydropyridine type, structurally related to felodipine. Clinical trials ha ve shown that the drug can be used to effectively control the blood pressur e in connection with cardiac surgical procedures. The compound is tailored to be a short-acting drug and, due to incorporation of an ester linkage int o the drug molecule, clevidipine is rapidly metabolized by ester hydrolysis . The pharmacokinetics of clevidipine and its primary metabolite, H 152/81, were studied in rats, rabbits, and dogs. In addition, the influence of the pharmacokinetics on the effect on mean arterial blood pressure was evaluat ed in anesthetized dogs. Compartmental nonlinear mixed effect regression an alysis was used to calculate the population mean and individual pharmacokin etics of clevidipine, whereas nonlinear regression analysis of individual d ata was used to determine the pharmacokinetics of the primary metabolite. A linked E-max model was fitted to the individual pharmacodynamic/pharmacoki netic data in dogs. According to the results, clevidipine is a high-clearan ce drug with a relatively small volume of distribution, resulting in an ext remely short half-life in all species studied. The median initial half-life of the individual value (Bayesian estimates) is 12, 20, and 22 s in the ra bbit, rat, and dog, respectively. The primary metabolite is a high-clearanc e compound in the dog, whereas it is a low-clearance compound in the rat. A significant gender difference in the clearance of the metabolite was obser ved in the rat. The mean maximum reduction in arterial blood pressure is 38 +/- 12% (E-max) and is achieved at 85 +/- 46 nM (EC50). The half-life for reaching equilibrium between the central and the effect compartment (T(1/2) k(eO)) is 47 +/- 49 s.